Human apolipoprotein (apo) A-I and apo E-3 possess different anti-atherogenic properties. Naturally-occurring mutants of apo A-I differ in their metabolism. Apo A-I mutants have been designed to elucidate the structure of apo A-I in phospholipid complexes, and we will determine the metabolism of these mutants and their effects on atherogenesis. Peptide mimics of apo A-I possess anti-atherogenic properties in vitro. We have shown that class A amphipathic helical peptide analogs inhibit atherosclerosis when injected into C57BL/6J mice fed an atherogenic diet, and orally administered all-D-residue peptide analogs inhibit atherosclerosis in LDL-receptor deficient (LDL-R null) mice on a Western diet. This project will investigate the in vivo effects of amphipathic helical peptide analogs possessing specific in vitro-determined anti-atherogenic properties. We will determine which specific properties (such as LCAT activation, cholesterol efflux, or protection from the effects of oxidation) are required for atherosclerosis inhibition in atherosclerosis-susceptible mice. Peptide analogs possessing a cationic domain analogous to those of apo E are able to lower plasma cholesterol rapidly in vivo. We have evidence that these peptide analogs clear atherogenic lipoproteins by a proteoglycan-mediated rapid uptake of peptide-lipoprotein complexes. We will test the hypothesis that incorporation of positively charged residues onto atherogenic lipoproteins will result in a rapid hepatic clearance of atherogenic lipoproteins in dyslipidemic mice, resulting in inhibition of atherosclerosis. Our current working hypothesis is that in vivo, two general mechanisms for atherosclerosis protection, reduction in atherosclerosis without changing levels of atherogenic lipoproteins, and reduction in atherogenic lipoproteins and atherosclerosis itself, can be achieved by altering surface properties of atherogenic lipoproteins. To study this concept, we propose a two-arm approach demonstrating: 1: the in vivo determinants of atherosclerosis protection by class A amphipathic peptides or apo A-I mutants that do not alter levels of atherogenic lipoproteins; and 2: the in vivo effects of administration of cationic amphipathic helical peptides that reduce plasma levels of atherogenic lipoproteins.